Losoxantrone is an active drug for the treatment of breast cancer. The published process (Showalter et al., J. Med. Chem. (1987) 30: 121-131; J. Heterocyclic Chem. (1989) 26: 85) requires the use of 2-[(hydrazinoethyl)amino]ethanol as a raw material. The limited availability of this raw material makes this published process for the manufacture of losoxantrone impractical. Furthermore, the current process needs a very tedious, costly, and environmentally hazardous chromatographic separation to isolate the desired regioisomer. There is a need, therefore, for improved methods of synthesis of losoxantrone and related compounds. The present invention provides new synthetic processes for the synthesis of losoxantrone and related compounds, which eliminates the need for the use of 2-[(hydrazinoethyl)amino]ethanol and the need for the chromatographic separation of the desired product.
Showalter et al., U.S. Pat. No. 4,556,654, issued Dec. 3, 1985 describes the synthesis of anthra[1,9-cd]pyrazol-6(2H)-ones of formulas 1 (losoxantrone) and 2: ##STR1## where X, X' and W may be H, OH, alkoxy, or Cl. Showalter et al. also describe the synthetic methods of Schemes A and B shown below. ##STR2## where Q, Q' and Q" are H, alkyl, benzyloxy, p-chlorobenzyloxy, or p-methoxybenzyloxy and X, X' and W are defined above.
Johnson and Showalter, U.S. Pat. No. 4,608,439, issued Aug. 26, 1986 describe a process for making anthra[1,9-cd]pyrazol-6 (2H) -ones from 1,2-dichloro-5, 8-distributed-9, 10-anthracenediones and a hydrazine, as shown in Scheme C. ##STR3## Beylin et al., U.S. Pat. No. 4,672,129, issued Jun. 9, 1987 describe an improved process for the preparation of anthra[1,9-cd]pyrazol-6(2H)-ones from 1,2-dichloro-5,8-distributed-9,10-anthracenediones via a chromatographic separation of isomers of formulas 3 and 4, as shown in Scheme D. ##STR4##
None of the above-cited references describe the methods of the present invention for the synthesis of anthrapyrazolone anticancer agents or the compounds of the present invention which are useful as intermediates for the synthesis of anthrapyrazolone anticancer agents.